ELEVATION OF INTRACELLULAR CYCLIC ADENOSINE-MONOPHOSPHATE INHIBITS THE EPIDERMAL GROWTH-FACTOR SIGNAL-TRANSDUCTION PATHWAY AND CELLULAR GROWTH IN PANCREATIC ADENOCARCINOMA CELL-LINES

Background. The epidermal growth factor (EGF) signal transduction path way, frequently activated in pancreatic cancer, is an important regula tor of cellular growth and transformation. This study examined whether activation of the cyclic adenosine monophosphate protein kinase ii pa thway may inhibit the EGF signal transduction pathway in pancreatic ca ncer cell lines. Methods. Human pancreatic cancer lines BxPC-3 and AsP C-1 were stimulated with EGF, forskolin, or both. Forskolin is a compo und that increases cyclic adenosine monophosphate levels. Assays of ce ll lines were then obtained for cellular growth (MTT assay), anchorage -independent growth (soft agar), and EGF-induced mitogen-activated pro tein kinase activation as measured by an in-gel kinase assay. Results, Treatment with forskolin resulted in inhibition of EGF-induced activa tion of mitogen-activated protein kinase activity (BxPC-3 78% inhibiti on and AsPC-1 70% inhibition, p < 0.005), diminished cellular prolifer ation (BxPC-3 92% inhibition and AsPC-1 86% inhibition, p < 0.001), an d formation of colonies in soft agar (BxPC-3 98% inhibition and AsPC-1 76% inhibition, p < 0.001). Forskolin did not inhibit EGF receptor au tophosphorylation or tyrosine kinase signaling in response to EGF. Con clusions. Forskolin-induced inhibition of mitogen-activated protein ki nase is associated with diminished pancreatic cancer cell proliferatio n in vitro. Use of strategies to increase cyclic adenosine monophospha te levels may have therapeutic application in pancreatic cancer.